CA2228997C

CA2228997C - Benzothiophene compounds

Benzothiophene compounds Download PDF

Info

Publication number: CA2228997C
Authority: CA; Canada
Prior art keywords: alkyl; compounds; compound; estrogen; formula
Prior art date: 1995-08-17
Legal status : Expired - Fee Related

Application number

CA002228997A

Other languages

English (en)

French (fr)

Other versions

CA2228997A1 (en

Inventor

Henry Uhlman Bryant

Stephen Sung Yong Cho

Timothy Alan Grese

Current Assignee

Eli Lilly and Co

Original Assignee

Eli Lilly and Co

Priority date

1995-08-17

Filing date

1996-08-13

Publication date

2002-07-30

1996-08-13 Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co

1997-02-27 Publication of CA2228997A1 publication Critical patent/CA2228997A1/en

2002-07-30 Application granted granted Critical

2002-07-30 Publication of CA2228997C publication Critical patent/CA2228997C/en

2016-08-13 Anticipated expiration legal-status Critical

Status Expired - Fee Related legal-status Critical Current

Links

FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title description 4
150000001875 compounds Chemical class 0.000 claims abstract description 145
239000000262 estrogen Substances 0.000 claims abstract description 50
229940011871 estrogen Drugs 0.000 claims abstract description 49
-1 1-thienyl Chemical group 0.000 claims abstract description 38
150000003839 salts Chemical class 0.000 claims abstract description 30
239000000583 progesterone congener Substances 0.000 claims abstract description 19
RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims abstract description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 15
208000037803 restenosis Diseases 0.000 claims abstract description 15
201000010260 leiomyoma Diseases 0.000 claims abstract description 14
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims abstract description 12
206010027304 Menopausal symptoms Diseases 0.000 claims abstract description 12
201000009273 Endometriosis Diseases 0.000 claims abstract description 11
206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 10
210000000329 smooth muscle myocyte Anatomy 0.000 claims abstract description 10
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 9
230000004663 cell proliferation Effects 0.000 claims abstract description 9
239000008194 pharmaceutical composition Substances 0.000 claims abstract description 9
125000001424 substituent group Chemical group 0.000 claims abstract description 9
208000024891 symptom Diseases 0.000 claims abstract description 8
208000010579 uterine corpus leiomyoma Diseases 0.000 claims abstract description 8
201000007954 uterine fibroid Diseases 0.000 claims abstract description 8
125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims abstract description 6
125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims abstract description 6
125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 6
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 6
125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims abstract description 5
125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 5
125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract description 4
230000002401 inhibitory effect Effects 0.000 claims abstract description 3
XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims abstract 4
125000001475 halogen functional group Chemical group 0.000 claims abstract 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
239000003085 diluting agent Substances 0.000 claims description 8
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
125000003386 piperidinyl group Chemical group 0.000 claims description 2
125000001624 naphthyl group Chemical group 0.000 claims 1
206010028980 Neoplasm Diseases 0.000 abstract description 22
208000001132 Osteoporosis Diseases 0.000 abstract description 11
230000001419 dependent effect Effects 0.000 abstract description 7
230000001575 pathological effect Effects 0.000 abstract description 6
201000011510 cancer Diseases 0.000 abstract description 4
230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
238000000034 method Methods 0.000 description 43
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
238000011282 treatment Methods 0.000 description 39
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
239000000203 mixture Substances 0.000 description 31
210000004027 cell Anatomy 0.000 description 28
238000006243 chemical reaction Methods 0.000 description 28
210000001519 tissue Anatomy 0.000 description 28
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
241001465754 Metazoa Species 0.000 description 25
239000000243 solution Substances 0.000 description 23
238000012360 testing method Methods 0.000 description 22
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239000002904 solvent Substances 0.000 description 19
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239000004480 active ingredient Substances 0.000 description 17
HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 17
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 16
230000012010 growth Effects 0.000 description 15
239000002253 acid Substances 0.000 description 14
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239000003795 chemical substances by application Substances 0.000 description 13
238000004587 chromatography analysis Methods 0.000 description 13
230000002357 endometrial effect Effects 0.000 description 13
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 12
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
241000700159 Rattus Species 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
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125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 10
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 10
239000003826 tablet Substances 0.000 description 10
201000010099 disease Diseases 0.000 description 9
239000000741 silica gel Substances 0.000 description 9
229910002027 silica gel Inorganic materials 0.000 description 9
238000001356 surgical procedure Methods 0.000 description 9
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
BFPYWIDHMRZLRN-SLHNCBLASA-N Ethinyl estradiol Chemical compound OC1=CC=C2[C@H]3CC[C@](C)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 BFPYWIDHMRZLRN-SLHNCBLASA-N 0.000 description 8
VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 8
239000006260 foam Substances 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 8
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
229920002472 Starch Polymers 0.000 description 7
206010067269 Uterine fibrosis Diseases 0.000 description 7
239000003638 chemical reducing agent Substances 0.000 description 7
125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
230000008569 process Effects 0.000 description 7
239000008107 starch Substances 0.000 description 7
235000019698 starch Nutrition 0.000 description 7
DNXHEGUUPJUMQT-UHFFFAOYSA-N (+)-estrone Natural products OC1=CC=C2C3CCC(C)(C(CC4)=O)C4C3CCC2=C1 DNXHEGUUPJUMQT-UHFFFAOYSA-N 0.000 description 6
101150041968 CDC13 gene Proteins 0.000 description 6
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 6
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 6
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
235000012000 cholesterol Nutrition 0.000 description 6
230000001076 estrogenic effect Effects 0.000 description 6
DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 description 6
229960002568 ethinylestradiol Drugs 0.000 description 6
239000012091 fetal bovine serum Substances 0.000 description 6
238000000338 in vitro Methods 0.000 description 6
150000002632 lipids Chemical class 0.000 description 6
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
230000035755 proliferation Effects 0.000 description 6
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UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 6
230000002792 vascular Effects 0.000 description 6
238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 5
108091003079 Bovine Serum Albumin Proteins 0.000 description 5
125000000217 alkyl group Chemical group 0.000 description 5
150000008064 anhydrides Chemical class 0.000 description 5
239000012911 assay medium Substances 0.000 description 5
WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 5
229910002092 carbon dioxide Inorganic materials 0.000 description 5
239000001768 carboxy methyl cellulose Substances 0.000 description 5
JKKFKPJIXZFSSB-CBZIJGRNSA-N estrone 3-sulfate Chemical compound OS(=O)(=O)OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 JKKFKPJIXZFSSB-CBZIJGRNSA-N 0.000 description 5
125000005843 halogen group Chemical group 0.000 description 5
239000012442 inert solvent Substances 0.000 description 5
239000007928 intraperitoneal injection Substances 0.000 description 5
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ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 4
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MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
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ODLMAHJVESYWTB-UHFFFAOYSA-N propylbenzene Chemical compound CCCC1=CC=CC=C1 ODLMAHJVESYWTB-UHFFFAOYSA-N 0.000 description 4
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JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
ARSRBNBHOADGJU-UHFFFAOYSA-N 7,12-dimethyltetraphene Chemical compound C1=CC2=CC=CC=C2C2=C1C(C)=C(C=CC=C1)C1=C2C ARSRBNBHOADGJU-UHFFFAOYSA-N 0.000 description 3
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229930182555 Penicillin Natural products 0.000 description 3
JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 3
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TZAVGZOZSPFAEO-UHFFFAOYSA-N [2-(dimethylamino)-6-methoxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone Chemical compound CN(C)C=1SC2=CC(OC)=CC=C2C=1C(=O)C(C=C1)=CC=C1OCCN1CCCCC1 TZAVGZOZSPFAEO-UHFFFAOYSA-N 0.000 description 3
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